Statin Use, Cholesterol Level, and Mortality Among Females With Breast Cancer

This cohort study evaluates the association of serum cholesterol level and statin use with breast cancer (BC)–specific and overall mortality in females with invasive BC.


Information on cholesterol and hormone receptor status
We gathered serum cholesterol, lipoprotein and triglyceride measurements and hormone receptor data from laboratory databases of Pirkanmaa, Southwest Finland and Helsinki-Uusimaa Hospital Districts Estrogen receptor (ER), progresterone receptor (PR) and ERBB2 status in tumor tissue was extracted from pathological reports of the primary tumor and metastases.We deemed ER and PR statuses negative if < 10% and positive if ≥ 10% of tumor cells were stained; we determined the ERBB2 status negative or positive according to the pathological reports.ER, PR and ERBB2 status were included in the analysis as dichotomous variables.
All measurements for serum total cholesterol, HDL, LDL and triglycerides were obtained from the laboratory databases.We determined median cholesterol concentrations for each calendar year separately using all measurements during that year.We used the latest available median for years with no measurements.We categorized cholesterol and other lipid parameter levels as normal or elevated according to the cardiovascular recommended target levels; 193.05 mg/dL for total cholesterol,46.33mg/dL for HDL, 115.83 mg/dL for LDL, and 150.44 mg/dL for triglyceride.To convert total cholesterol, HDL, and LDL to millimoles per liter, multiply by 0.0259; triglycerides to millimoles per liter, multiply by 0.0113.
We estimated the changes in blood cholesterol levels after the start of statin use by calculating the median cholesterol levels before and after the first year of statin purchase.Measurements from the first year of statin use were excluded as the exact time for the initiation of drug use is not known based on purchase data.In total, 980 patients began statin use after BC diagnosis.Median cholesterol level decreased subsequently in 781 participants while the level remained similar or increased compared to pre-statin purchase levels in 199 participants.

Comorbidities
Information on diagnoses of hypertension, hypercholesterolemia, coronary artery disease and diabetes mellitus (DM) during 1995-2013 were obtained from the Finnish Care Register for Health Care (HILMO).Each comorbidity was recognized based on the condition-specific ICD-10 code.The participant was categorized to have the condition (e.g.diabetes), if she had the diagnosis recorded at least once at any time during the study period.Each variable was included in the analysis as dichotomous variable.
We calculated Charlson Comorbidity Index (CCI) based on diagnoses in the HILMO database (e.g., diabetes) and drug purchase data from the Finnish Social Insurance Institution (SII) database (e.g., antidiabetic drugs).CCI was included in the analysis as continuous variable.

Information on medication use
We linked the study cohort to the national SII prescription database to collect person-level information on cholesterollowering, antihypertensive, antidiabetic, and anticoagulant medication purchases during 1995-2015.Usage status for each drug group was determined separately for each follow-up year based on recorded purchases.All participants remained non-users until the first year of recorded purchase.After that they were categorized as users until the end of follow-up.
Post-diagnostic usage status was included into analysis as dichotomous, time-dependent variable that was updated for each follow-up year separately, starting from the year of breast cancer diagnosis.Pre-diagnosis usage was analyzed as dichotomous time-independent variable based on medication usage between 1995 and year of breast cancer diagnosis.
For statins, we also considered statin dose.We added together all statin purchases on a given year for yearly total milligram (mg) amount of use for each statin and standardized the cumulative use between different statins by dividing yearly purchased amount (mg) with drug-specific Defined Daily Dose (DDD) as listed by the World Health Organization (WHO) To estimate the yearly dosage of statin use, we calculated an intensity variable by dividing the cumulative yearly DDD amount with the cumulative duration of use.Intensity of statin use was determined separately for each follow-up year after breast cancer diagnosis, and analyzed as categorical variable stratified by tertile cut-points.
For pre-diagnosis usage, intensity of statin use was calculated by dividing statin DDDs between 1995 and year of diagnosis with number of years with recorded purchases in that same time frame.Pre-diagnosis intensity was analyzed as time-independent categorical variable stratified by tertile cut-points.

Mammography screening
We used the National Mass Inspection Registry to obtain the number of mammography screens the participants had attended before BC diagnosis.This variable was included in the analysis as continuous variable.

eTable 3. ATC-codes used to detect drug prescription database of the Finnish Social Insurance Institution. Study
cohort of 13,378 Finnish women with breast cancer (BC).

eTable 4. The risk of breast cancer (BC) death by serum HDL and triglycerides levels before and after BC diagnosis.
Study cohort of 13,378 females with breast cancer (BC) diagnosis in Finland from 1995 to2013.Cox proportional hazards regression model adjusted for age at BC diagnosis, number of mammography screening rounds attended before BC diagnosis, tumor extent, tumor histological characteristics, primary treatment, coronary artery disease, diabetes, hypertension, Charlson Comorbidity Index, hormone receptor status, and use of antihormonal therapy after BC diagnosis.Cut-off values: Total cholesterol higher than 193.05;Triglycerides higher than 150.44;HDL lower than 46.33;LDL higher than 115.83 (mg/dL) c HDL tertiles before BC diagnosis: first, 57.14 or less; second, higher than 57.14 to 71.62; third, higher than 71.62;Triglycerides tertiles before BC diagnosis: first, 81.42 or less;, second, higher than 81.42 to 119.47; third, higher than 119.47 (mg/dL).Total cholesterol tertiles after BC diagnosis: first, 181.47 mg/dL or less; second, higher than 181.47 to 212.36 mg/dL; third, higher than 212.36 mg/dL.Triglycerides tertiles after BC diagnosis: first, 84.07 mg/dL or less; second, higher than 84.07 to 121.68 mg/dL; third, higher than 121.68 mg/dL.HDL tertiles after BC diagnosis: first, 56.37 mg/dL or less; second, higher than 56.37 to 71.43 mg/dL; third, higher than 71.43 mg/dL.LDL tertiles after BC diagnosis: first, 100.39 mg/dL or less; second, higher than 100.39 to 128.69 mg/dL; third, higher than 128.69 mg/dL.
a Calculated using a b d eTable 5.

The risk of breast cancer (BC) death by statin use after BC diagnosis, lag- time analysis.
Abbreviations: HR, hazard ratio.aCalculated using a Cox proportional hazards regression model adjusted for age at BC diagnosis, number of mammography screening rounds attended before BC diagnosis, tumor extent, tumor histological characteristics, primary treatment, coronary artery disease, diabetes, hypertension, Charlson Comorbidity Index, hormone receptor status, and use of antihormonal therapy after BC diagnosis.eTable 6.

The risk of overall death by serum total cholesterol and LDL levels before and after BC diagnosis.
Study cohort of 13,378 females with breast cancer (BC) diagnosis in Finland from 1995 to2013.Cox proportional hazards regression model adjusted for age at BC diagnosis, number of mammography screening rounds attended before BC diagnosis, tumor extent, tumor histological characteristics, primary treatment, coronary artery disease, diabetes, hypertension, Charlson Comorbidity Index, hormone receptor status, and use of antihormonal therapy after BC diagnosis.Total cholesterol tertiles after BC diagnosis: first, 181.47 mg/dL or less; second, higher than 181.47 to 212.36 mg/dL; third, higher than 212.36 mg/dL.Triglycerides tertiles after BC diagnosis: first, 84.07 mg/dL or less; second, higher than 84.07 to 121.68 mg/dL; third, higher than 121.68 mg/dL.HDL tertiles after BC diagnosis: first, 56.37 mg/dL or less; second, higher than 56.37 to 71.43 mg/dL; third, higher than 71.43 mg/dL.LDL tertiles after BC diagnosis: first, 100.39 mg/dL or less; second, higher than 100.39 to 128.69 mg/dL; third, higher than 128.69 mg/dL.

The risk of overall death by serum HDL and triglycerides levels before and after BC diagnosis.
Study cohort of 13,378 females with breast cancer (BC) diagnosis in Finland from 1995 to2013.Calculated using a Cox proportional hazards regression model adjusted for age at BC diagnosis, number of mammography screening rounds attended before BC diagnosis, tumor extent, tumor histological characteristics, primary treatment, coronary artery disease, diabetes, hypertension, Charlson Comorbidity Index, hormone receptor status, and use of antihormonal therapy after BC diagnosis.HDL tertiles before BC diagnosis: first, ≤ 57.14, or less; second, higher than 57.14 to 71.62; third, higher than > 71.62; Triglycerides tertiles before BC diagnosis: first, ≤ 81.42 or less; second, higher than 81.42 to 119.47; third, higher than 119.47 (mg/dL) d Total cholesterol tertiles after BC diagnosis: first, 181.47 mg/dL or less; second, higher than 181.47 to 212.36 mg/dL; third, higher than 212.36 mg/dL.Triglycerides tertiles after BC diagnosis: first, 84.07 mg/dL or less; second, higher than 84.07 to 121.68 mg/dL; third, higher than 121.68 mg/dL.HDL tertiles after BC diagnosis: first, 56.37 mg/dL or less; second, higher than 56.37 to 71.43 mg/dL; third, higher than 71.43 mg/dL.LDL tertiles after BC diagnosis: first, 100.39 mg/dL or less; second, higher than 100.39 to 128.69 mg/dL; third, higher than 128.69 mg/dL.
a c

eTable 8. The risk of overall death by statin use and with adjustment for serum total cholesterol, LDL, HDL and triglycerides before and after BC diagnosis.
Study cohort of 13,378 females with breast cancer (BC) diagnosis in Finland from 1995 to2013.Cox proportional hazards regression model adjusted for age at BC diagnosis, number of mammography screening rounds attended before BC diagnosis, tumor extent, tumor histological characteristics, primary treatment, coronary artery disease, diabetes, hypertension, Charlson Comorbidity Index, hormone receptor status, and use of antihormonal therapy after BC diagnosis.

Subgroup analysis: the risk of breast cancer (BC) death by increased serum cholesterol level and statin use after breast cancer diagnosis.
Study cohort of 13,378 females with breast cancer (BC) diagnosis in Finland from 1995 to2013.Calculated using a Cox proportional hazards regression model adjusted for age at BC diagnosis, number of mammography screening rounds attended before BC diagnosis, tumor extent, tumor histological characteristics, primary treatment, coronary artery disease, diabetes, hypertension, Charlson Comorbidity Index, hormone receptor status, and use of antihormonal therapy after BC diagnosis.
Abbreviations: ER, estrogen receptor; PR, progesterone receptor; HR, hazard ratio.a Total cholesterol higher than 193.05 mg/dL b